Alnylam Reports Positive ALN-TTR02 Clinical Data

Alnylam Pharmaceuticals, Inc. has announced the achievement of positive clinical results from its Phase I trial with ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The data were presented today in a seminar by Alnylam scientists at Boston University School of Medicine. Results from this study show that administration of ALN-TTR02 leads to robust knockdown of serum TTR protein levels of up to 94%; the overall results were highly significant (p<0.00001 by ANOVA). Suppression of TTR, the disease-causing protein in ATTR, was found to be rapid, dose dependent, durable, and specific after just a single dose. Alnylam recently reported that it has initiated a Phase II study of ALN-TTR02 in patients with ATTR and has guided that its goal is to start a pivotal trial in 2013.

“We are very excited with these new ALN-TTR02 results, where we have achieved very robust effects, including up to 94% reduction of serum TTR and a nearly 80% level of suppression sustained at one month with just a single dose. These results document an unprecedented level of clinical activity for RNAi therapeutics and strongly support advancement of this innovative program to meet the needs of ATTR patients,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “Knockdown of circulating TTR is a validated endpoint in ATTR based on data from patients receiving liver transplants. Further, evidence from other systemic amyloidotic diseases shows that as little as a 50 percent reduction of the disease-causing protein can result in disease improvement or stabilization. Accordingly, these data with ALN-TTR02 provide key human proof of concept with associated clinical relevance as we advance this medicine to patients for the treatment of ATTR, a debilitating orphan genetic disease. We look forward to continuing to share clinical data from our ALN-TTR02 program, and, assuming positive results in the current Phase II study, we plan to advance to a pivotal trial in 2013.”

“I am very encouraged by these new data with ALN-TTR02, an RNAi therapeutic for the treatment of ATTR. Specifically, I am impressed with the almost complete knockdown of TTR after just a single dose of drug, which is important since TTR protein reduction in patients with ATTR has the potential to delay or even reverse disease progression with associated clinical benefits,” said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose. “I look forward to the continued advancement of RNAi therapeutics in clinical trials for the treatment of ATTR, as there are currently few options for patients suffering from this devastating disease.”

The Phase I trial of ALN-TTR02 was conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, and enrolled 17 healthy volunteer subjects. The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-TTR02, with subjects being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50 mg/kg. In addition, pharmacodynamic activity was evaluated with serial measurements of serum TTR protein levels through at least day 56. Serum TTR levels were measured by an ELISA assay and also by a turbidometric assay method.

Preliminary data from this study showed that a single dose of ALN-TTR02 resulted in rapid, dose-dependent, durable, and specific knockdown of serum TTR levels. Even at doses as low as 0.15 mg/kg, substantial serum TTR suppression was achieved, with a mean 81.9% knockdown at nadir. At a dose of 0.30 mg/kg, an 86.8% mean knockdown was achieved at nadir, with a mean 66.7% reduction still observed 28 days post-dose. In the one subject treated at 0.50 mg/kg, knockdown of 93.8% was observed at nadir, with 76.8% reduction maintained at day 28. ALN-TTR02 exhibited a rapid onset of action; over 50% knockdown in TTR was achieved by day three in all of the 0.15, 0.30, and 0.50 mg/kg subjects, and nadir levels were achieved by day 10 to 14. In addition, time courses for TTR reduction showed highly consistent pharmacologic effects, with minimal inter-subject variability in maximal levels of TTR suppression (<5% relative standard deviation among 0.15 and 0.30 mg/kg subjects). Using a turbidometric assay method to measure TTR, 3 of 4 (75%) subjects receiving ALN-TTR02 in the 0.30 and 0.50 mg/kg dose groups showed undetectable levels of serum TTR on one or more post-dose days. As expected, serum TTR reductions were highly correlated with parallel changes in retinol binding protein (RBP) (r2=0.83) and vitamin A levels (r2=0.86). The effects of ALN-TTR02 were also determined to be specific, as subjects (n=6) treated at a 0.4 mg/kg dose of an siRNA targeting PCSK9 in the identical lipid nanoparticle (LNP) formulation showed no significant serum TTR reduction in a separate, recently completed Phase I study. As a result of the positive pharmacology seen at doses as low as 0.15 mg/kg, dosing at 0.50 mg/kg was limited to one patient, allowing for the start of the Phase II study with ALN-TTR02 in ATTR patients. Alnylam believes that these robust and durable knockdown data support a once-a-month or possibly once-every-other month dosing regimen, and intends to examine this further in the ongoing Phase II study.

ALN-TTR02 was found to be generally safe and well tolerated in this Phase I study, consistent with Alnylam’s broader clinical experience with LNP-formulated siRNA which now includes 102 patients or subjects, 334 total doses administered, and a length of treatment exceeding two years. There were no serious adverse events or discontinuations in the study related to ALN-TTR02 and there were no significant adverse events associated with drug up through 0.30 mg/kg. A moderate acute infusion reaction was observed in one subject receiving ALN-TTR02 at 0.50 mg/kg who was able to complete dosing with slowing of the infusion rate. There were no laboratory abnormalities, including no changes in liver function tests, cytokines, or C-reactive protein (CRP).

“In our continued efforts to advance RNAi therapeutics to patients, we believe these data with ALN-TTR02 establish new industry milestones. First, these results demonstrate the highly robust level of target gene knockdown and attractive pharmacologic profile achievable with RNAi therapeutics. Further and for the first time, we have generated data using a control siRNA from a parallel study documenting the specificity for RNAi therapeutics in humans,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Finally, these results mark important progress in our overall ‘Alnylam 5x15’ product strategy efforts. While there is more to do in our efforts to bring RNAi therapeutics to patients in need, we are very encouraged by this significant step forward.”

Alnylam is advancing ALN-TTR02 in a Phase II study which is designed as an open-label, multi-center, multi-dose, dose-escalation trial expected to enroll approximately 20 ATTR patients. Patients will be enrolled into cohorts of increasing doses and will receive drug once every four weeks for two cycles. The primary objectives of the study are to evaluate the safety and tolerability of multiple doses of ALN-TTR02 and to measure clinical activity based on serial measurement of circulating serum TTR levels.

The microfluidic device with interlinking modules containing human-derived heart, liver, skeletal muscle and nervous system cells was able to maintain cellular viability and record cellular function in real-time for 28 days.